HIV replication in the CNS results in widespread activation of microglia and astrocytosis and neuronal damage. Highly active antiretroviral therapy (HAART) decreases plasma and in some cases CSF viral load, delays the onset of immunosuppression (AIDS) and improves cognitive function in HIV-infected individuals. However, there is evidence that HAART has been less effective in lowering virus replication in the CNS than in the blood, perhaps because not all drugs cross the blood-brain barrier. Thus, the brain may be a reservoir where HIV remains latent and undergoes resurgent replication upon cessation of antiretroviral therapy, either because of unacceptable side effects or noncompliance. In this Project a well-characterized SIV/macaque model will be used to examine the effects of combination antiretroviral therapy (CART) with a non-nucleoside reverse transcriptase inhibitor (PMPA) and a protease inhibitor (nelfinavir) on CNS virus replication, inflammation and neurodegeneration. Our hypothesis is that combination antiretroviral therapy (CART) with drugs that suppress viral load in the plasma to below detectable levels will only partly suppress virus replication in the brain, and that low-level virus replication in the CNS will result in production of neurotoxic viral and cellular products and only partial amelioration of neurodegeneration. We further hypothesize that upon cessation of antiviral therapy there will be rapid resurgence of CNS virus replication with development of inflammation and neurodegeneration. Aim 1 will determine the extent to which CART treatment of SIVinfected macaques suppresses CNS expression of viral neurotoxic proteins, infiltration and/or activation of macrophages,microglia, astrocytes and endothelial cells, and production of proinflammatory/neurotoxic chemokines and cytokines in the brain. Aim 2 will determine whether CART normalizes the homeostatic balance between expression of proapoptotic and antiapoptotic signaling molecules in the brain, and inhibits the development of acute and/or chronic neurodegeneration Aim 3 will determine whether there is independent replication of specific genotypes in the CNS when virus replication is suppressed in the periphery. Aim 4 will determine whether cessation of antiretroviral therapy results in more rapid development of CNS inflammation and neurodegeneration and whether renewed virus replication in the CNS after withdrawal of antiretroviral drugs occurs from pre-existing virus and/or renewed entry of virus from the periphery.